Dopamine neurons for aversive learning – DARLING

The three partners combined diverse technical approaches spanning from in vivo and in vitro electrophysiology to behavioral paradigms modeling associative learning. DARLING gave us the opportunity to recently develope the in vivo head-restrained recording to record and manipulate sub-population of dopamine neurons in behaving animals. Using those in vivo integrated approaches, we have first analyzed the functional organization of neuronal circuits linking the hippocampus to the dopamine neurons of the ventral tegmental area. We have characterized how synaptic glutamatergic inputs (in vitro and in vivo) modulate the excitability of dopamine neurons before and after hippocampal manipulation. We have use viral transfection and optogenetic approaches in vitro and in vivo to drive the activity of sub-population of dopamine neurons. Finally we will evaluate if light-induced activation of distinct dopamine neurons populations drives aversive learning.

Our first exciting result obtained from the DARLING project is that the ventral hippocampus, which is mainly involved in the integration of contextual and emotional information, is able to drive the activity of dopamine neurons. The bed nucleus of the stria terminalis is a key relay in this excitatory response between the ventral hippocampus and the dopamine neurons. We recently discovered that synaptic plasticity induced by tetanic stimulation of the ventral hippocampus, was transferring from the BNST to the VTA. The next step was to work on the behavioral implications of these synaptic changes. Those studies allow us to get a better understanding of how the change in synaptic transmission of this new neuronal circuit, first potentiates the activity of the dopamine neurons, but also change the perception of sensorial stimuli, drugs or natural rewards in physiological or pathological condition (addiction, anxiety..). The DARLING project provides new evidence of anatomical and functional differences in the BNST (bed nucleus of the stria terminalis) –VTA (ventral tegmental area) pathway between mice and rats. This recently published study further highlights the importance of taking into account the choice of animal model for experimental design and interpretation and imposes a change in the last aim of DARLING where the use of transgenic mice was proposed.

Specific subpopulations of VTA dopamine neurons projecting to defined neuronal structures involved in aversive associative learning (e.g. amygdala) are strongly regulated by the ventral hippocampus (vHPC), a brain region that integrates contextual information's and regulates emotional behavior.The development of a long-term potentiation at the ventral subiculum/Bed nucleus of the stria terminalis synapses causes a persistent (several days) hyperactivity of dopamine neurons, induce a behavioral sensitization to the effects of cocaine and a decrease in the state of anxiety of the animal. Our work characterized the neural circuits and mechanisms of synaptic plasticity that underlie the behavioral effects of cocaine, and opens new perspectives, in particular understanding how a change in the synaptic state of dopamine neurons can alter the perception of sensory stimuli in physiological condition (natural rewards) or pathological (addiction, anxiety disorder). Our research project will provide important glimpses on how VTA dopamine neurons achieve these processes to ultimately regulate associative aversive learning, and transgenic rat model are currently used in the laboratory to answer this question.

DARLING gave us the opportunity to present our work in the form of posters and oral communication at numerous national and international congresses. DARLING gave rise to 6 publications:

We have anatomically and functionally characterized the control exerted by the hippocampus onto dopaminergic neurons (4 publications)
Kaufling J., Girard D., Maitre M, Leste-Lasserre T., Georges F. Species-specific diversity in the anatomical and physiological organization of the BNST-VTA pathway. Mar 6. doi: 10.1111/ejn.13554
• Glangetas C*, Massi L*, Fois G.R. *, Jalabert M., Girard D., Diana M., Yonehara K., Roska B., Xu C., Lüthi A., Caille S. Georges F. NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis. Nat Comm. 2017 Nat Commun. 2017 Feb 20;8:14456. doi: 10.1038/ncomms14456.
• Glangetas C, Georges F. Pharmacology of the Bed Nucleus of the Stria Terminalis. Current Pharmacology Reports 2017 2 (6), 262-270
• Glangetas C, Fois G.R., Jalabert M., Lecca S., Valentinova K., Meye F.J., Diana M., Faure P., Mameli M., Caille S., Georges F. Ventral Subiculum Stimulation Promotes Persistent Hyperactivity of Dopamine Neurons and Facilitates Behavioral Effects of Cocaine. Cell Reports. 2015 ; 13(10), 2287-2296.

We characterized the heterogeneity of dopaminergic systems in response to drug abuse (2 publications):


• Creed M, Kaufling J, Fois GR, Jalabert M., Yuan T., Lüscher C, Georges F*., BelloneC*. Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs. J Neurosci. 2016 36(42):10759-10768 *These authors share senority
• Valentinova, K.*, Lecca, S.*, Meye, F.J.*, Marion-Poll, L., Maroteaux, M.J., Musardo, S., Moutkine, I., Gardoni, F., Huganir, R., Georges, F., Mameli, M. Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula. Nat. Neurosci. 2015 ; 18 (3), 376-378.

A key feature of human and animal behavior is to learn from environmental stimuli to efficiently adapt. The ability to minimize contact with aversive experience is a hallmark of adaptive behavior and recent studies have demonstrated a key role of the ventral tegmental area (VTA) dopamine neurons in this process. However the underlying neuronal circuits and neuronal mechanisms are still largely unknown. Interestingly, specific subpopulations of VTA dopamine neurons projecting to defined neuronal structures involved in aversive associative learning (e.g. prefrontal cortex and amygdala) are strongly regulated by the ventral hippocampus (vHPC), a brain region that integrates contextual information's and regulates emotional behavior. The main objective of this grant proposal is to determine how sub-populations of dopamine neurons receiving specific inputs from the vHPC and projecting to specific target contribute to aversive associative learning.
With the hypothesis that the neuronal response of anatomically distinct dopamine neurons to conditioned stimuli will serve as a teaching signal for aversive associative learning, the DARLING project gathers 3 academic partners and is developed around 2 objectives: first to characterize how distinct populations of VTA dopamine neurons integrate excitatory drive from the vHPC and second to identify and manipulate dopamine neurons sub-populations necessary for aversive learning.
To reach these objectives, the partners will combine diverse technical approaches spanning from in vivo and in vitro electrophysiology to behavioral paradigms modeling associative learning. Using in vivo integrated approaches, we will investigate how the firing of distinct dopamine neuronal populations related to stimuli predicting aversive events contributes to aversive learning. We will first analyze the functional organization of neuronal circuits linking the hippocampus to the VTA. The experiments proposed in this task will characterize how synaptic glutamatergic inputs (in vitro and in vivo) modulate the excitability of dopamine neurons before and after aversive learning. We will use viral transfection and optogenetic approaches in vitro and in vivo to drive specific glutamatergic relays from the vHPC to the VTA. Finally we will evaluate if light-induced activation of distinct dopamine neurons populations drives aversive learning. Partner expertise, solid preliminary results, and the scientific program should ensure the project success. A major goal in neuroscience is to determine how changes in the neuronal activity of brain circuits contribute to sensory integration and generate teaching signals to regulate behavioral responses. Our research project will provide important glimpses on how VTA dopamine neurons achieve these processes to ultimately regulate associative aversive learning.